The compound (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine represented by the formula 1
is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Compound 1 has anti-tumor properties that are pharmacologically mediated through inhibition of c-Met/HGFR which is involved in the regulation of growth and metastatic progression of a wide variety of tumors types, and ALK which implicated in the pathogenesis of ALCL (anaplastic large cell lymphoma). Compound 1 is disclosed in International Patent Application No. PCT/IB2005/002837 and U.S. patent application Ser. No. 11/212,331, both of which are herein incorporated by reference in their entirety. Additionally, the racemate of compound 1 is disclosed in International Patent Application No. PCT/IB05/002695 and U.S. patent application Ser. No. 11/213,039, both of which are herein incorporated by reference in their entirety.
Human cancers comprise a diverse array of diseases that collectively are one of the leading causes of death in developed countries throughout the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of cancers is caused by a complex series of multiple genetic and molecular events including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of cancer are both diverse and complex, each cancer type has been observed to exhibit common traits and acquired capabilities that facilitate its progression. These acquired capabilities include dysregulated cell growth, sustained ability to recruit blood vessels (i.e., angiogenesis), and ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100: 57-70). Therefore, the ability to identify novel therapeutic agents that 1) inhibit molecular targets that are altered during cancer progression or 2) target multiple processes that are common to cancer progression in a variety of tumors presents a significant unmet need.
An extensive body of literature indicates that c-Met/HGFR is one of the most frequently mutated or otherwise abnormally activated RTKs in various human cancers (Christensen J G, Burrows J, Salgia R. c-Met as a target in human cancer and characterization of inhibitors for therapeutic intervention. Cancer Letters 2005; 225: 1-26). Tumor types in which c-Met/HGFR was reported to be genetically altered by mutation or gene amplification include but are not limited to oncology indications with a strong unmet medical need such as renal, metastatic colorectal, glioma, non-small cell lung, gastric, and head and neck cancers (Christensen J G, Burrows J, Salgia R. c-Met as a target in human cancer and characterization of inhibitors for therapeutic intervention. Cancer Letters 2005; 225: 1-26).
HGFR mutations have been implicated in renal carcinoma (See, for example, L. Schmidt, K. Junker, N. Nakaigawa, T. Kinjerski, G. Weirich, M. Miller, et al., Novel mutations of the MET proto-oncogene in papillary renal carcinomas, Oncogene 1999; 18: 2343-2350; L. Schmidt, F. M. Duh, F. Chen, T. Kishida, G. Glenn, P. Choyke, et al., Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas, Nat. Genet. 1997; 16: 68-73; L. Schmidt, K. Junker, G. Weirich, G. Glenn, P. Choyke, I. Lubensky, et al., Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene, Cancer Res. 1998; 58: 1719-1722). HGFR mutations have been tied to head and neck carcinoma (See, for example, M. F. Di Renzo, M. Olivero, T. Martone, A. Maffe, P. Maggiora, A. D. Stefani, et al., Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas, Oncogene 2000; 19: 1547-1555; D. M. Aebersold, O. Landt, S. Berthou, G. Gruber, K. T. Beer, R. H. Greiner, Y. Zimmer, Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapytreated squamous cell cancer of the oropharynx, Oncogene 2003; 22: 8519-8523). HGFR mutations have been linked to lung carcinoma (See, for example, P. C. Ma, T. Kijima, G. Maulik, E. A. Fox, M. Sattler, J. D. Griffin, et al., c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions, Cancer Res. 2003; 63: 6272-6281; P. C. Ma, S. Jagdeesh, R. Jagadeeswaran, E. A. Fox, J. G. Christensen, G. Maulik, et al., c-MET expression/activation, functions, and mutations in non-small cell lung cancer, Proc. Am. Assoc. Cancer Res. 2004; 63: 1875.
Additionally, HGFR mutations have been implicated in other indications including but not limited to childhood hepatocellular carcinomas, human gastric cancer, scirrhous type stomach cancer, colorectal cancer, and malignant melanoma. (See, for example, W. S. Park, S. M. Dong, S. Y. Kim, E. Y. Na, M. S. Shin, J. H. Pi, et al., Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas, Cancer Res. 1999; 59: 307-310; J. H. Lee, S. U. Han, H. Cho, B. Jennings, B. Gerrard, M. Dean, et al., A novel germ line juxtamembrane Met mutation in human gastric cancer, Oncogene 2000; 19: 4947-4953; A. Lorenzato, M. Olivero, S. Patane, E. Rosso, A. Oliaro, P. M. Comoglio, M. F. Di Renzo, Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion, Cancer Res. 2002; 62: 7025-7030; H. Kuniyasu, W. Yasui, Y. Kitadai, H. Yokozaki, H. Ito, E. Tahara, Frequent amplification of the c-met gene in scirrhous type stomach cancer, Biochem. Biophys. Res. Commun. 1992; 189: 227-232; M. F. Di Renzo, M. Olivero, A. Giacomini, H. Porte, E. Chastre, L. Mirossay, et al., Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer, Clin. Cancer Res. 1995; 1: 147-154; T. Hara, A. Ooi, M. Kobayashi, M. Mai, K. Yanagihara, I. Nakanishi, Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization, Lab. Invest. 1998; 78: 1143-1153).
The relationship of HGFR mutations to function and oncogenic potential has also been established (See for example, M. Jeffers, L. Schmidt, N. Nakaigawa, C. P. Webb, G. Weirich, T. Kishida, et al., Activating mutations for the met tyrosine kinase receptor in human cancer, Proc. Natl. Acad. Sci. USA 1997; 94: 11445-11450; M. Jeffers, M. Fiscella, C. P. Webb, M. Anver, S. Koochekpour, G. F. Vande Woude, The mutationally activated Met receptor mediates motility and metastasis, Proc. Natl. Acad. Sci. USA 1998; 95: 14417-14422).
Finally, HGFR mutations have been implicated in and studied in mouse tumors (See for example, H. Takayama, W. J. LaRochelle, R. Sharp, T. Otsuka, P. Kriebel, M. Anver, et al., Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor, Proc. Natl. Acad. Sci. USA 1997; 94: 701-706; T. Otsuka, H. Takayama, R. Sharp, G. Celli, W. J. LaRochelle, D. P. Bottaro, et al., c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype, Cancer Res. 1998; 58: 5157-5167; M. I. Gallego, B. Bierie, L. Hennighausen, Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways, Oncogene 2003; 22: 8498-8508; C. R. Graveel, Y. Su, L. M. Wang, M. Fiscella, T. Lino, c. Birchmeier, et al., Tumorigenic effects of activating Met mutations in a knock-in mouse model, Proc. Am. Assoc. Cancer Res. 2004; 44: 5102).
NPM-ALK, an oncogenic fusion protein variant of the Anaplastic Lymphoma Kinase, which results from a chromosomal translocation is implicated in the pathogenesis of human anaplastic large cell lymphoma (Pulford K, Morris S W, Turturro F. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 2004; 199: 330-58). The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of ALCL have been well defined (Weihua Wan, et. al. Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large cell lymphoma cells. Blood First Edition Paper, prepublished online Oct. 27, 2005; DOI 10.1182/blood-2005-08-3254).
The inappropriate activation of c-Met/HGFR (including wild-type c-Met) is also implicated in dysregulation of multiple tumor oncogenic processes such as mitogenesis, survival, angiogenesis, invasive growth, and especially in the metastatic process (Christensen et al, 2005). Furthermore, the expression of c-Met and HGF, its sole, high-affinity ligand, were demonstrated to correlate with poor prognosis or metastatic progression in a number of major human cancers (Christensen et al, 2005). NPM-ALK is implicated in the dysregulation of cell proliferation and apoptosis in ALCL lymphoma cells (Pulford et al, 2004).